SUMMARY OF PROJECT 2 The goal of this project is to transform the management of pancreatic cancer (PanCa), a devastating disease that is most often diagnosed late, when curative therapies are no longer possible. Our strategy is to target the disease at three key stages: premalignant, locally advanced and metastatic, using photodynamic therapy (PDT) in combination with systemic therapy. We will build on our previous findings of PDT-induced tumor necrosis in PanCa patients, developing new treatment strategies that combine PDT with appropriately scheduled systemic chemotherapy to treat local and metastatic disease. We will also explore new treatment options for early pancreatic malignancies and precursor lesions, including intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN) from which many PanCa arise. Following on from our phase I clinical studies of CT-guided percutaneous PDT for locally advanced PanCa, Project 2 will move to the minimally invasive approach of endoscopic ultrasound (EUS)-guided PDT, with the potential for outpatient therapy with improved safety and healthcare costs. The goals will be realized in three aims. AIM 1 will establish, in a phase II study, the efficacy of EUS-PDT using verteporfin (benzoporphyrin, BPD) to ablate solid tumors of the pancreas. Clinical contrast CT-based treatment planning will be used to deliver patient-specific PDT. This aim will also establish the safety of giving chemotherapy almost immediately after PDT. AIM 2 will evaluate the novel combination of PDT and MM-398 (liposomal irenotecan, a topoisomerase inhibitor in phase III trials for metastatic PanCa), using the optimized treatment schedule identified in Aim 1 of Project 3 in collaboration with Merrimack Pharma. The hypothesis for the basis of synergistic mechanisms is that MM-398 reduces hypoxia and enhances PDT, while PDT destroys ABCG2 transporters and enhances MM-398 retention. Since single therapies alone are ineffective in PanCa, it is hypothesized that this combination strategy will enhance survival of patients who have locally advanced and/or metastatic disease. In AIM 3 we will study the efficacy of EUS-PDT in the treatment of premalignant cystic tumors of the pancreas. We will establish the use of fluorescence dosimetry and pre-PDT contrast CT to maximize PDT-induced cyst ablation. The immediate impact of this project will be to improve the care of patients with PanCa, and more broadly the findings will establish a clinical framework to translate new nanomedicine and combination-based targeted therapeutic discoveries for cancer. Potential public health benefits: The clinical studies described in Aims 1 and 2 provide new minimally invasive treatment options aimed at improving the length and quality of life in patients with PanCa. In Aim 3, we will develop a new ablative treatment option for patients with pancreatic cystic tumors, which will reduce the inconvenience and anxiety for patients of serial imaging and need for long-term follow up or surgery, with significant cost-savings.